Effect of a novel NK1 receptor selective antagonist (NKP608) on citric acid induced cough and airway obstruction

https://doi.org/10.1016/j.pupt.2003.08.002Get rights and content

Abstract

The effects of an orally administered novel and selective NK1 antagonist, NKP608, on cough and airway obstruction, induced by citric acid in guinea pigs, were investigated. Guinea pigs were pre-treated with 0.03, 0.3 and 1 mg kg−1 of NKP608, the NK2 antagonist, SR48968 or both 2 h prior to challenge with citric acid (0.6 M) for a 10 min period. Guinea pigs pre-treated with 0.03, 0.3 and 1  mgkg−1 of NKP608 exhibited a significant reduction of 77, 74 and 79%, respectively, in the numbers of cough compared to vehicle pre-treated animals (P<0.05). SR48968, 10 mg kg−1, alone did not significantly affect the citric acid-induced cough but when co-administered with 1 mg kg−1 of NKP608, there was a significant 90% reduction in cough. NKP608 did not significantly reduce the citric acid-induced increase in Penh at any of the doses used. SR48968 significantly reduced the citric acid induced airway obstruction by about 50%. However, when SR48968 was co-administered with NKP608, there was a greater (73%) decrease in the airway obstruction compared with SR48968 alone. These data show that NKP608, a selective NK1 receptor antagonist, is a potent inhibitor of citric acid induced cough in guinea pigs and may therefore have value in the therapy of clinical cough.

Introduction

It is generally accepted that the cough reflex is initiated through activation of vagal afferent nerves. However, the predominant vagal afferent nerve subtype that is involved in the cough reflex is yet to be elucidated. Whilst there is evidence to suggest a central role for capsaicin sensitive fibres in cough [1], [2], there is also indication that the Aδ-fibres may also be important in this regard [3].

Experimentally induced cough is increasingly being used as a model for the understanding of cough and evaluation of novel anti-tussive agents. Exposure to capsaicin, a predominantly C-fibre ending stimulant, causes cough in man and guinea pigs [2], [4]. Moreover, inhalation of citric acid is also known to cause cough in several species including man and can also cause sneezing and bronchoconstriction [4], [5], [6], [7]. Both citric acid and capsaicin have also been shown to excite bronchial C-fibre receptors. The non-myelinated, C-fibre afferents contain the tachykinins substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) which act on NK1, NK2, NK3 receptors, respectively [8].

There is a body of evidence supporting the notion that sensory nerve fibres, through an efferent function, are involved in the mechanisms of cough. Indeed, several studies have demonstrated an important role for tachykinins in cough. Exposure of guinea pigs to SP has been shown to result in cough [9], [10]. Also the NK1 receptor antagonist, FK888, has been shown to inhibit cough induced by stimuli such as SP, smoke, citric acid or histamine [5], [10], [11]. Moreover, the non-peptide receptor NK1 antagonist CP99,994 inhibited both capsaicin and mechanically induced cough in guinea pigs and cats, respectively [12]. The neutral endopeptidase inhibitor (NEP), phosphoramidon, enhances SP and histamine-induced cough [11], [13]. Finally, exposure of individuals, with either colds or upper respiratory tract infections, but not normal subjects, to SP induces cough [14]. Although these studies highlight an important role for SP and the NK1 receptor in the cough response some studies have failed to demonstrate a significant role for substance P and NK1 receptors in cough [15], [16]. The reasons for this disparity in the literature are not clearly understood. However, it is possible that differences in the experimental procedure, such as time from dosing of drug to time of airway challenge, ways by which cough was induced and difference in potencies and pharmacokinetics of NK1 receptor antagonists may all account for the different observations.

In this study, we have evaluated the effect of a novel, potent and selective NK1 antagonist, NKP608, on citric acid induced cough and airway obstruction in the guinea pig. The in vitro pharmacology of NKP608 has been recently characterized [17], [18]. NKP608 has been previously shown to bind with high affinity to hrNK1 receptors (pKi, 8.96±0.02) compared to hrNK2 and hrNK3 receptors (pKi, values of 6.1±0.01 and 6.25±0.02, respectively) [18]. Moreover, in guinea pig tracheal strips, NKP608 was shown to antagonize Sar [9] met(O2)–SP induced contraction in a non-surmountable fashion (pA2, 7.7±0.1) [18]. However, at the NK2 receptors, NKP608 was shown to be less potent and to exhibit surmountable antagonism (pA2, 6.0±0.1) [18].

Section snippets

Experimental set-up

The methods described in this study were subjected to Home Office approval and performed under the Animal (Scientific Procedures) Act, 1986.

Conscious, unrestrained, male Dunkin Hartley guinea pigs, weighing 250–500 g, were placed individually in a transparent plastic whole body plethysmograph (Buxco, Tro, NY) and exposed to a nebulized aqueous solution of citric acid. The aerosol was produced by a DeVilbiss AeroSonic ultrasonic nebulizer (DeVilbiss, Somerset, PA, USA) and had an aerodynamic

Drugs

Drugs used were citric acid (BDH laboratory, Poole UK), NKP608 and SR48968 (synthesized at Novartis Horsham Research Centre), dimethylsulphoxide (Sigma, Dorset, UK), Cremophor (a derivative of castor oil and ethylene oxide) (Sigma, Dorset, UK). NKP608 and SR48968 were dissolved in a solution made up of 2% DMSO, 17% Cremophor and 81% Saline. Citric acid was made up in 0.9% saline.

Effect of exposure to 0.2, 0.4 and 0.6 M citric acid on cough

Exposure of guinea pigs to 0.2, 0.4 and 0.6 M citric acid induced 7.4±1.5, 10.3±2.2, 13±2.8 coughs, respectively, (Fig. 1). All doses of citric acid-induced significant cough responses (P<0.05) compared with saline challenge where no cough was induced (Fig. 1). Although the cough response to citric acid was concentration dependent, it is a shallow concentration response curve and there was no significant difference in the number of cough between the different concentrations (P>0.05). The

Discussion

The data in this study show that exposure of guinea pigs to citric acid induces a cough response and airway obstruction and that these can be recorded simultaneously in the same animal. Furthermore, pretreatment of animals with the novel NK1 receptor antagonist, NKP608, results in a significant inhibition of the citric acid-induced cough but not the airway obstruction. In contrast, pre-treatment of animals with the NK2 antagonist, SR48968, did not significantly reduce the cough response but

Acknowledgements

This work was funded by Novartis Horsham Research Centre, Novartis Pharmaceutical, UK. We would also like to thank Sana Amine and Ohood Al-Humaidy for their help in preparing this manuscript and Kuwait University for their support.

References (32)

  • T. Kondo et al.

    An increase in the threshold of citric acid-induced cough during chest wall vibration in healthy humans

    Jpn J Physiol

    (1998)
  • F.L. Ricciardolo et al.

    Bronchoconstriction induced by citric acid inhalation in guinea pigs: role of tachykinins, bradykinin, and nitric oxide

    Am J Respir Crit Care Med

    (1999)
  • D. Regoli et al.

    Receptors and antagonists for substance P and related peptides

    Pharmacol Rev

    (1994)
  • H. Kohrogi et al.

    Neutral endopeptidase inhibitors potentiate substance P and capsaicin induced cough in awake guinea pigs

    J Clin Invest

    (1988)
  • Y. Ujiie et al.

    Evidence for substance P as an endogenous substance causing cough in guinea-pigs

    Am Rev Respir Dir

    (1993)
  • K. Sekizawa et al.

    Role of substance P in cough during bronchoconstriction in awake guinea pigs

    Am J Respir Crit Care Med

    (1995)
  • Cited by (0)

    View full text